Primary biliary cirrhosis is a chronic systemic disease characterized by progressive intrahepatic cholestasis secondary to inflammatory destruction of septal and interlobular bile ducts. The disease ultimately leads to cirrhosis and is usually fatal. Permanent spontaneous remissions have not been reported, and currently there is no known effective treatment. We propose to bring to completion a proposective randomized control trial designed to assess the efficacy of D-penicillamine in PBC. Well defined diagnostic criteria and randomization of patients, according to duration of disease and the presence of absence of cirrhosis and/or portal hypertension, has resulted in highly comparable drug and control groups. A favorable referral pattern has resulted in an impressive number of patients entering our trial (228 as of 3-1-81). The patients have demonstrated excellent cooperation and compliance with the study protocol and they have provided us with relatively long-tem follow-up observations on a large number of patients. It is unlikely that another trial of this size and duration of patient follow-up will again be undertaken at one institution. This trial enables a unique opportunity to study a relatively uncommon disease for which there is currently no treatment. We have enjoyed excellent cooperation from many major medical centers in this country. In addition to the therapeutic trial, we have addressed a number of complications associated with PBC and report our results in the Progress Section. We have maintained careful and regular monitoring for adverse side effects and drug toxicity. This information should be of value to others administering D-penicillamine for diseases such as rheumatoid arthritis, Wilson's disease, cystinuria, etc. Our long-term objective is to establish a rationale treatment program for PBC devoid of significant side effects or toxicity. The favorable referral pattern and large patient study population provides us an excellent opportunity to carry out this treatment trial.